PROJECT SUMMARY: Psychotic symptoms occur in ~ 40-60% of individuals with Alzheimer Disease (AD with psychosis, AD+P). Numerous studies have found that the AD+P phenotype is associated with more rapid cognitive decline than AD subjects without psychosis (AD-P). Current, empirically developed, treatments for psychosis in AD have limited efficacy, do not alter the more rapid disease progression, and are associated with substantial toxicity, including excess mortality. Because the annual incidence of psychosis in AD is only ~ 10%, there is a window of opportunity to intervene to prevent psychosis onset if resilience factors can be identified. Multiple brain imaging studies have shown that relative to AD+P, subjects with AD-P have preserved indices of cortical synaptic function, especially in the dorsolateral prefrontal cortex (DLPFC). Our recent genetic and proteomic findings in patients and model systems have converged on a possible mechanism to explain this synaptic resilience in AD-P: Preservation of postsynaptic density (PSD) protein levels in DLPFC. First, using targeted mass spectrometry (MS) in DLPFC grey matter homogenates from mild to moderate AD subjects, we found a robust increase in homogenate levels of canonical PSD proteins in AD-P subjects relative to both AD+P and Control subjects. Second, we identified and independently confirmed a polygenic protection against psychosis in AD which included an allele associated with reduced DLPFC expression of TOM1L2. TOM1L2 is an adaptor protein that facilitates degradation of synaptic proteins via actin-based endocytic trafficking. Finally, in the APPswe/PSEN1dE9 mouse model of A? overproduction, we found that reduction of Kalrn, a Rac1/RhoA guanine nucleotide exchange factor that regulates endocytic trafficking, elevated canonical PSD protein levels in cortical homogenates, preserved these proteins' levels in PSD enrichments, and protected against psychosis-associated behaviors. We thus hypothesize: resilience to psychosis onset in AD is conferred by preservation of protein levels in PSD enrichments, due to reduced trafficking of PSD proteins for degradation, and can be used to identify novel therapeutics. We will test this hypothesis in three Aims: Aim 1) To determine if PSD proteome alterations and gene-protein interactions are associated with resilience to AD+P; Aim 2) To test the effect of reduction in Tom1l2 on the synaptic proteome in a mouse model, and; Aim 3) To use computational chemogenomics to identify drugs that induce synaptic proteome compensations which confer resilience to AD+P, providing for rational prevention and/or treatment. The above aims benefit from the tight integration and leveraging of Multiple PIs with expertise in the synaptic pathology of psychosis (Sweet), the neuropathology of AD (Kofler), and the use of computation for novel therapeutic discovery (Wang). Upon completion, we will have delineated the synaptic protein compensations associated with resilience to psychosis in AD and discovered leads to compounds that generate synaptic resilience for future testing in future studies.